Influence of Process Variable and Physicochemical Properties on the Granulation Mechanism of Mannitol in a Fluid Bed Top Spray Granulator

This study investigated the influence of specific process variables, including the hydroxypropyl cellulose (HPC) binder solution atomization, on the fluidized bed top spray granulation of mannitol. Special attention was given to the relationship between wetting and the granule growth profile. The atomization of the HPC binder solution using a binary nozzle arrangement produced droplets of decreasing size as the atomization pressure was increased, while changes in the spray rate had little effect on the mean droplet size. Increasing the HPC binder concentration from 2 to 8% w/w increased the binder droplet size and was most likely attributed to higher solution viscosity. The top spray granulation of mannitol showed induction type growth behavior. Process conditions like high spray rate, low fluidizing air velocity and binder solution concentration that promote the availability of HPC binder solution at the surface of the particles appeared to be key in enhancing nucleation and growth of the granules. Increasing the bed moisture level, up to a certain value, reduced the contribution of attrition to the overall growth profile of the granule and, more significantly, produced less granule breakage on drying. It was observed that the mean granule size could be reduced as much as 40% between the end of granulation and the end of drying for lower initial bed moisture level despite a shorter drying phase. High atomization pressure, especially when maintained during the drying phase, contributed substantially to granule breakage.     

Influence of process variable and physicochemical properties on the granulation mechanism of mannitol in a fluid bed top spray granulator

This study investigated the influence of specific process variables, including the hydroxypropyl cellulose (HPC) binder solution atomization, on the fluidized bed top spray granulation of mannitol. Special attention was given to the relationship between wetting and the granule growth profile. The atomization of the HPC binder solution using a binary nozzle arrangement produced droplets of decreasing size as the atomization pressure was increased, while changes in the spray rate had little effect on the mean droplet size. Increasing the HPC binder concentration from 2 to 8% w/w increased the binder droplet size and was most likely attributed to higher solution viscosity. The top spray granulation of mannitol showed induction type growth behavior. Process conditions like high spray rate, low fluidizing air velocity and binder solution concentration that promote the availability of HPC binder solution at the surface of the particles appeared to be key in enhancing nucleation and growth of the granules. Increasing the bed moisture level, up to a certain value, reduced the contribution of attrition to the overall growth profile of the granule and, more significantly, produced less granule breakage on drying. It was observed that the mean granule size could be reduced as much as 40% between the end of granulation and the end of drying for lower initial bed moisture level despite a shorter drying phase. High atomization pressure, especially when maintained during the drying phase, contributed substantially to granule breakage.     

Melt granulation in fluidized bed: a comparative study of spray-on versus in situ procedure

Objective: The aim of this study was to investigate the influence of process parameters, binder content and binder addition method on characteristics of the granules obtained by melt granulation (MG) in fluidized bed.

Methods: Spray-on experiments were performed according to 2³ full factorial design. The effect of binder content, molten binder feed rate, and spray air pressure on granule size and size distribution, granule shape, ?owability and drug release rate was investigated. In the in situ experiments, the influence of binder particle size and binder content was evaluated. Solid-state characterization was performed by means of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy.

Results: Size of the granules obtained by spray-on procedure was significantly influenced by binder content and spray air pressure, while the width of particle size distribution was mainly affected by binder feed rate. Spray air pressure showed the most significant influence on granule shape. It was shown that smooth and spherical particles with good flow properties may be obtained by both procedures, spray-on and in situ MG. The results obtained indicated the influence of agglomeration mechanism on granule sphericity, with higher degree of granule sphericity observed when immersion and layering was the dominant mechanism. Paracetamol release from granulates was very rapid, but after compression of the granules into tablets, drug release was considerably slower. Solid-state analysis confirmed that the physical form of the granulate components remained unaffected after the MG process.

Conclusion: The results presented indicate that MG in fluidized bed could be a good alternative to conventional granulation techniques.     

流化床喷雾造粒产品粒度分布的影响因素研究

在一下端直径188mm、上端直径396mm、高1000mm的倒锥形流化床喷雾造粒器内,以碳酸钙(CaCO3)粉末作为制药工业上的替代性原料,以明胶作为粘结剂,实验研究了床层温度、流化气速、雾化空气压等因素对造粒产品粒度分布的影响。结果表明,在本实验范围内,造粒产品颗粒的平均粒径随着流化气速、床层温度、雾化空气压的增大而减小,且粒度分布趋向于发散。     

Granulation in a Fluidized Bed II Effect of Binder Amount on the Final Granules

Abstract

There are many parameters affecting the properties of the final granules prepared in a fluidized bed. In this study one of the product parameters, quantity of the binder, has been studied for its effect on the final granule size, size distribution and friability

Determination of granule size change as a function of binder quantity leaded us to study the growth mechanisms during fluidized bed granulation. Two mechanisms are suggested;

1) Snowballing of primary granules (nuclei)

2) Agglomeration of primary granules

It has been shown that there is a critical amount of binder at which the formation of the primary granules comes to an end if more binder is added to the system. Then granule growth occurs by agglomeration of the primary granules. The physical properties of the granules formed before and after this critical binder concentration varies significantly     

Study of granule growth kinetics during in situ fluid bed melt granulation using in-line FBRM and SFT probes

Objective: The aim of this work was to study the granule growth kinetics during in situ fluid bed melt granulation process using real-time particle size measurement techniques. In addition, the usefulness of these techniques during scale-up of melt granulation was evaluated.

Materials and methods: Focused beam reflectance measurement (FBRM) and spatial filtering technique (SFT) probes were used within the process chamber of fluid bed granulator for real-time in-line granule size analysis.

Results: The results demonstrated that the use of in-line particle size probes in fluid bed granulator during the process offers an insightful view of granule growth and allows in-process monitoring of granule chord length changes. The effect of selected critical parameters (binder content, inlet air temperature and product endpoint temperature) on the granule growth was clearly presented by in-line measurements in a laboratory scale. A comparison of granule size measurements from both FBRM and SFT probes showed similar particle growth trends, which were in close correlation to the product temperature. Comparable trends in end granule particle size were observed when comparing different in-line, at-line and off-line particle size measurements.

Conclusion: The in-line FBRM and SFT probes were successfully employed in in situ fluid bed melt granulation process to study the influence of critical formulation/process parameters on the granule growth kinetics. The scale-up experiment confirmed the potential of these in-line granule size measurement techniques as a viable tool for process monitoring during the transfer of granulation to the larger scale or another manufacturing site/equipment.     

Optimizing a wet granulation process to obtain high-dose sustained-release tablets with Compritol 888 ATO

Context: Niacin (vitamin B3) is a micronized active pharmaceutical ingredient (API) with poor flow properties making the production of high-dose sustained-release tablets by direct compression a challenge.

Objective: We evaluated various wet granulation processes as a simple and efficient approach to obtain high-dose (500 and 1000?mg) niacin sustained-release lipid matrix tablets.

Materials and methods: A high melting-point lipid (Compritol® 888 ATO) was used as the sustained-release agent. Tablets were prepared by various wet granulation techniques, with different process parameters and binder concentrations to identify the optimal process conditions.

Results: A binder (PVP) was needed to increase particle bonding and tablet strength. Process parameters, such as spray rate and quantity of liquid, had only a slight impact on the properties of the granules and resultant tablets, in the presence of low binder concentrations. Increasing binder concentration improved granule wetting, resulting in significant granule growth and improved flow properties. Sustained-release over 12?h was observed for all the compacted granules, irrespective of the drug dose. The sustained-release kinetics for 1000?mg niacin matrix tablets with Compritol 888 produced with the identified optimal parameters were similar to those for the market reference product, Niaspan® FCT 1000?mg. The tablets were stable for up to six months when stored at 25 and 40?°C.

Conclusions: Wet granulation with Compritol 888 presents an effective approach to improve material flow and compressibility. High-dose lipid matrix tablets with sustained release profiles can be successfully produced.     

Manufacture of Slow-Release Matrix Granules by Wet Granulation with an Aqueous Dispersion of Quaternary Poly(meth)acrylates in the Fluidized Bed

ABSTRACT

Slow-release matrix granules were manufactured in the fluidized bed using an aqueous dispersion of quaternary poly(meth)acrylates (Eudragit® RS 30 D) as binder for granulation. A factorial design was carried out to investigate the influence of the following parameters, spraying rate, applied polymer amount, and inlet air temperature, on various granule properties. Prerequisites for a slow release of the model drug theophylline are high spraying rate, high amount of polymer, and low inlet air temperature. No considerable decrease of the drug release rate can be achieved without a subsequent curing of the dry granules. A clear correlation exists between the moisture content of the fluidized bed, indicated by the terminal moisture content (TMC), and the mean dissolution time for 80% of the drug (MDT₈₀).     

Evaluation of Binder Activities on the Physical Properties and Compression Characteristics of Granules Prepared by Two Different Modes

Abstract

The effects of various binders and binder concentrations in production of granules by two different granulation modes were first investigated on the basis of the granule size distribution. Increasing the amount of binder produced larger and less friable granules associated with a decrease in flow rate and an increase in angle of repose. The strength of granules prepared by either the wet conventional or the fluidized bed was a function of its mean particle diameter and of binder-content with the later factor being more predominant. The inclusion of paracetamol into the placebo formula decreased the granule crushing strength. The effect was more pronounced with smaller granules and decreased with increasing granule size.

The rank order of the paracetamol-PVP granules crushing strength was reversed for the tensile strength of their corresponding tablets, viz., the paracetamol-PVP tablets prepared from fluidized granulation exhibited a higher tensile strength than that compressed from wet granules. A new parameter index “ø_b index” which combines tablet characteristics is presented. The index proposed allowed an overall simpler quantitative evaluation of a binder activity. Incorporated into this index are four tablet parameters, viz., tensile strength, percent porosity, median dissolution time, and percent friability. A higher “ø_b, index” infers better physical properties of tablets. Binders used in this study are then classified according to this index: PVP > gelatin > PEG 6000.     

Aluminium-Magnesium Hydroxide Tablets: Effect of Processing and Composition of Granulating Solution on the Granule Properties and In Vitro Antacid Performance

Abstract

Wet granulation experiments on aluminium-; magnesium hydroxide; mannitol blends were carried out, in order to produce chewable antacid tablets.

The influence of binder solvent, of type and concentration of polyvinylpyrrolidone as a binder and of granulating and drying equipment on the granule and tablet characteristics was investigated.

Water as a binder solvent offered several advantages over the use of alcohol. The use of high molecular weight polyvinylpyrrolidone reduced the antacid capacity and caused some manufacturing problems.

The granulating equipment (high shear granulator or planetary mixer) and the drying technique (oven or fluidized bed) had no major influence on the granule and tablet characteristics.     

Air invasion in a granular layer immersed in a fluid: morphology and dynamics

We investigate the morphology and dynamics of the region invaded by air injected at the bottom of an immersed granular bed. Previous experimental results point out the formation of a fluidized zone with a parabolic shape which does not depend, in the stationary regime, on the injection flow-rate. By tilting the experiment, we can tune the effective gravity in the system. We show that it does not affect significantly the morphology either. A numerical study made it possible to access the typical height and width of the structure, which are governed by the relative effects of gravity and capillarity. After a brief review on this subject, we propose first, new experimental observations on the air invasion regimes and on the morphology of the fluidized zone, in particular its growth dynamics; then, we complement the previous numerical study by considering the influence of the bottom boundary condition. In particular, we quantify the morphology of the invaded region when the gas is injected in the bulk, thus when air is likely to propagate downwards. These results are of practical importance in the prediction of the morphology of gas invasion in soils, from $\hbox {CO}_2$ sequestration to pollutant propagation.     

Using Experimental Design to Optimize the Process Parameters in Fluidized Bed Granulation

In this study many parameters were screened for a small-scale granulation process for their effect on the yield of granules between 75 and 500 μm and the geometrical granule mean size (d50). First a Plackett-Burman design was applied to screen the inlet air temperature, the inlet flow rate, the spray rate, the nozzle air pressure, the nozzle spray diameter, and the nozzle position. The Plackett-Burman design showed that the key process parameters were the inlet flow rate and the spray rate and probably also the inlet air temperature. Afterward a fractional factorial design (2^5?2) was applied to screen the remaining parameters plus the nozzle aircap position and the spraying time interval. The fractional factorial design showed that the nozzle air pressure was also important. As the target values for the granule yield (between 75 and 500 μm) and the geometric mean granule size (between 300 and 500 μm) were reached during the screening experiments, further optimization was not considered necessary.     

Granulation in a Fluidized Bed II Effect of Binder Amount on the Final Granules

There are many parameters affecting the properties of the final granules prepared in a fluidized bed. In this study one of the product parameters, quantity of the binder, has been studied for its effect on the final granule size, size distribution and friability

Determination of granule size change as a function of binder quantity leaded us to study the growth mechanisms during fluidized bed granulation. Two mechanisms are suggested;

1) Snowballing of primary granules (nuclei)

2) Agglomeration of primary granules

It has been shown that there is a critical amount of binder at which the formation of the primary granules comes to an end if more binder is added to the system. Then granule growth occurs by agglomeration of the primary granules. The physical properties of the granules formed before and after this critical binder concentration varies significantly     

流化床喷雾造粒颗粒强度的影响因素研究

颗粒强度作为流化床喷雾造粒产品的重要评价指标,对其影响因素的实验研究具有重要的现实意义。本文在一间歇锥形流化床喷雾造粒器中,以食用小麦淀粉为原料,以明胶的水溶液为粘结剂,实验研究了流化气速、床层温度、喷嘴雾化空气压力、粘结剂浓度对喷雾造粒颗粒强度的影响。结果表明,在本实验范围内,流化气速对颗粒强度的影响显著,床层温度、粘结剂浓度对颗粒强度也有较大的影响,而且均是非单调的。但喷嘴雾化空气压力与颗粒强度之间存在正向相关性。     

喷动流化床喷雾造粒过程实验研究

为了研究喷雾造粒过程中影响颗粒粒径生长速率的因素,本文中在自建的喷动流化床上,以玻璃珠为晶种,工业级碳酸钾溶液为涂敷液,对流化气速、喷动气速、床层温度、溶液流量和浓度等因素对颗粒生长速率的影响进行了实验研究。实验结果表明,颗粒的生长速率随流化气速、喷动气速、床层温度的增大先增大后减小;随溶液浓度、流量的增大而增大。     

Manufacture of slow-release matrix granules by wet granulation with an aqueous dispersion of quaternary poly(meth)acrylates in the fluidized bed

Slow-release matrix granules were manufactured in the fluidized bed using an aqueous dispersion of quaternary poly(meth)acrylates (Eudragit® RS 30 D) as binder for granulation. A factorial design was carried out to investigate the influence of the following parameters, spraying rate, applied polymer amount, and inlet air temperature, on various granule properties. Prerequisites for a slow release of the model drug theophylline are high spraying rate, high amount of polymer, and low inlet air temperature. No considerable decrease of the drug release rate can be achieved without a subsequent curing of the dry granules. A clear correlation exists between the moisture content of the fluidized bed, indicated by the terminal moisture content (TMC), and the mean dissolution time for 80% of the drug (MDT₈₀).     

Characteristics of piroxicam granules prepared by fluidized bed hot melt granulation

The aim of this study was to investigate the granulation of piroxicam by fluidized bed hot melt method using polyethylene glycol 4000 as the hydrophilic carrier and spray dried lactose as the fluidizing substrate. The effects of the spray nozzle air flow rate, axial position of the spray nozzle and load of fluidizing substrate on granules properties were investigated using a Box Behnken factorial design. The dependent variables evaluated were the mean particle size distribution, drug content and flow properties of the granules. The granule sizes ranged from 453.5?µm to 894.7?µm and piroxicam content was above 83.2%. However, the response surface ANOVA showed that sizes and piroxicam content were not affected by the granulation conditions and microscopy evidenced the presence of piroxicam crystals on granules surface. On the other hand, ANOVA showed that the granules flow properties were affected at the significance level of 5%. Thermal and infrared analysis showed that there was no interaction of piroxicam with carriers during the process. The dissolution profile of piroxicam was remarkably improved. Therefore, the results confirm the high potential of the fluidized bed hot melt granulation technique to obtain granules with enhanced drug solubility and release rates.     

The effect of the wetting droplets size on power consumption during drum granulation

Changes of torque during fine material (foundry dolomite) granulation in a horizontal drum granulator at changing wetting parameters were studied. The variable parameters were droplet diameter and wetting of granular material. The bed of loose material was sprayed during feeding, at a constant liquid flow rate V_l = 0.012 m³/h. The size of wetting liquid droplets was changed using different rates of air flow through pneumatic spraying nozzles in the range from V_p = 1.0 to 3.0 m³/h and applying a sprinkler which supplied (drop-wise) the liquid uniformly along the entire drum length. In each test, instantaneous values of torque on the granulator shaft were measured in 1 s time intervals. The effect of droplet size and moisture content of the bed of granular material on torque in the whole granulation cycle was estimated. It was found that bed wetting conditions had a significant influence on the nucleation and growth of agglomerates. A minimum (boundary) size of liquid droplets, at which the bed is not transformed into granulated material, depends on the total amount of liquid supplied at the wetting stage. Changes of torque during the drum granulation are a good representation of the phenomena related to the transformation of wetted feed into granulated product and can be an easy indicator of the process.The work was carried out within the project no. 4 T09C 023 22. financed by the State Committee for Scientific Research in the years 2002–2005.     

Preparation of Essential Oils Loaded Granule by Melt Granulation

Abstract

A comparative study on three granulation methods; melt granulation, fluidized bed granulation and wet granulation was performed to fabricate an essential oils loaded granule. The granule properties such as particle size distribution and the loading efficiency of anethole from fennel and cinnamaldehyde from cinnamon showed that the melt granulation in a high shear mixer was the most feasible method among the three methods.

In melt granulation, the granule particle size was well controlled by polyethylene glycol 6000 (PEG) content of which the optimum value was found to De 20%. Impeller speed and massing time in high shear mixer had small contribution to the particle growth when PEG content was optimized, while PEG particle size had some effect. Finer PEG powder improved the uniformity of granule size. Moreover, the cooling method of the hot mass affected the final granule properties significantly. The cooling with a fluid bed dryer was the best method.

Both of the retention rates of anethole and cinnamaldehyde in the final granule were more than 95% of initial doses irrespective of cooling method. Further, the adoption of a fluid bed dryer enabled very rapid cooling of hot granule with negligible loss of essential oils.     

Using experimental design to optimize the process parameters in fluidized bed granulation

In this study many parameters were screened for a small-scale granulation process for their effect on the yield of granules between 75 and 500 μm and the geometrical granule mean size (d50). First a Plackett-Burman design was applied to screen the inlet air temperature, the inlet flow rate, the spray rate, the nozzle air pressure, the nozzle spray diameter, and the nozzle position. The Plackett-Burman design showed that the key process parameters were the inlet flow rate and the spray rate and probably also the inlet air temperature. Afterward a fractional factorial design (2^5-2) was applied to screen the remaining parameters plus the nozzle aircap position and the spraying time interval. The fractional factorial design showed that the nozzle air pressure was also important. As the target values for the granule yield (between 75 and 500 μm) and the geometric mean granule size (between 300 and 500 μm) were reached during the screening experiments, further optimization was not considered necessary.